The use of animals as models for the behaviour of materials administered to humans is well established. One area of such use is in the testing of vaccines. One class of vaccines which currently is available is the so-called conjugate vaccines, in which a strongly-immunogenic protein is coupled to weakly- or non-immunogenic bacterial polysaccharide, so as to elicit an immune response to the bacterial polysaccharide upon administration of the conjugate. One particular example is conjugation of diphtheria toxoid to the capsular polysaccharide of Haemophilus influenzae type b (PRP-D), as described in U.S. Pat. Nos. 4,496,538 and 4,619,828.
It has been observed when testing these conjugate vaccines in mice and subsequently testing the vaccines in infants, a much higher immune response was achieved in humans than predicted by the mouse testing. For the same immune response, PRP-D needed to be administered in mice at about 1/5th of the human infant dose level, whereas, if there was a true dose/weight relation, the mouse dose would be about 1/300 of the human infant dose level. In fact, we have observed that doses less than or equal to 1/25 of a human dose do not induce an immune response.
It has been demonstrated (ref. 1) that infants must be vaccinated with both diphtheria toxoid and PRP-CRM (a mutant diphtheria toxin) to induce an anti-PRP response. A similar effect has been observed in rhesus monkeys (ref. 2). These experiments indicated that the simultaneous or prior immunization with the carrier protein may affect the anti-PRP response induced by conjugate vaccines. These results may serve to explain the discrepancies observed above between mouse data and human data, since infants are typically vaccinated with a DTP combination (diphtheria-tetanus-pertussis) vaccine before or at the same time as they are vaccinated with PRP-conjugates. Mice tested with PRP-conjugate would not have been administered the DTP or D component, because there was considered no reason to do so.